The studies proposed in this application will determine, at a molecular level, the toxicity of xenobiotics that are N-acetylated and will further define the relationship between the risk of toxicity and the acetylator phenotype of liver cells. The objectives of the proposed study are: 1) to evaluate the capacity of primary cultures of hepatocytes to N-acetylate xenobiotics and to reflect in this in vitro system the genetically-determined acetylator polymorphism; 2) to determine the cytotoxic and genotoxic potential of compounds that are metabolized by N-acetyltransferase; and 3) to seek a correlation, within a species, between the rate of nepatocyte acetylation and the genotoxicity of compounds that are N-acetylated. Metabolically active hepatocytes will be obtained by perfusion of the liver and the capacity of these cells in primary culture to N-acetylate will be quantified using sulfamethazine, a known substrate of the polymorphic N-acetyltransferase. The extent of interaction of substrates of N-acetyltransferase and their metabolites with nepatocyte DNA will be monitored directly for some compounds by measurement of DNA binding and indirectly for others by autoradiographic or density gradient centrifugation measurements of the DNA repair resulting from DNA damage.